1,4-dioxane

Endpoint summary

Description of key information

The acute oral and acute inhalation toxicity was investigated in studies performed comparable to the relevant OECD guidelines (401 and 403), resulting in an LD50 of approximately 5150 mg/kg bw, and an LC0 of 155 mg/L for 1 hour (which corresponds to 38.75 mg/L for 4 hours), respectively.

Key value for chemical safety assessment

Acute toxicity: via oral route

Link to relevant study records

Reference

Endpoint:

acute toxicity: oral

Type of information:

experimental study

Adequacy of study:

key study

Study period:

1973

Reliability:

2 (reliable with restrictions)

Rationale for reliability incl. deficiencies:

study well documented, meets generally accepted scientific principles, acceptable for assessment

Qualifier:

equivalent or similar to guideline

Guideline:

OECD Guideline 401 (Acute Oral Toxicity)

Principles of method if other than guideline:

BASF-Test

GLP compliance:

no

Test type:

standard acute method

Limit test:

no

Species:

rat

Strain:

not specified

Sex:

male/female

Details on test animals or test system and environmental conditions:

TEST ANIMALS
- Source: no data
- Age at study initiation: no data
- Weight at study initiation (mean): 226 g (males); 197 g (females)


ENVIRONMENTAL CONDITIONS
no data

Route of administration:

oral: gavage

Vehicle:

water

Details on oral exposure:

VEHICLE
- Concentration in vehicle: 30 %, 16 %, and 2 % (v/v)

MAXIMUM DOSE VOLUME APPLIED: 6 mL/animal

Doses:

200, 1600, 3200, 4000, 5000, and 6400 µL/kg bw (corresponding to approx. 206, 1648, 3296, 4120, 5150, and 6592 mg/kg bw) (recalculation of doses based on relative density of 1.03)

No. of animals per sex per dose:

5

Control animals:

no

Details on study design:

- Duration of observation period following administration: 7 days
- Frequency of observations and weighing: Weighing was performed only at the beginning of the study for dose calculation. Observation of clinical signs was performed several times on the day of administration and once daily afterwards with the exception of weekends and on holidays.
- Necropsy of survivors performed: yes
- Other examinations performed: clinical signs, pathology

Statistics:

No statistics were performed.

Key result

Sex:

male/female

Dose descriptor:

LD50

Effect level:

ca. 5 150 mg/kg bw

Based on:

test mat.

Mortality:

6592 mg/kg bw: 10/10 animals died within 48 hours
5150 mg/kg bw: 5/10 animals died within 7 days
At the lower doses between 4120 and 206 mg/kg bw no mortality was observed.

Clinical signs:

other: 6592 mg/kg bw: immediately after administration accelerated respiration, squatting posture and in some animals abdominal position were observed. After 5 min atony and apathy, after 10 min abdominal and lateral position, back posture, eye discharge and nar

Gross pathology:

Deceased animals:
- heart: acute dilatation; lungs: venous hyperemia, slightly edematous; stomach: bloody ulcerations; intestines: hematinized black contents, diarrheic; liver: pale; kidneys: pale; blood: coagulopathy.
Sacrificed animals:
- without abnormalities.

Mortality:

			Dead animals / treated animals after
Dose (mg/kg bw/d)	Conc. (%)	No of animals	1 h	24 h	48 h	7 d
6592	30	5 males	0/5	1/5	5/5	5/5
		5 females	0/5	3/5	5/5	5/5
5150	30	5 males	0/5	0/5	0/5	0/5
		5 females	0/5	1/5	1/5	5/5
4120	30	5 males	0/5	0/5	0/5	0/5
		5 females	0/5	0/5	0/5	0/5
3296	30	5 males	0/5	0/5	0/5	0/5
		5 females	0/5	0/5	0/5	0/5
1648	16	5 males	0/5	0/5	0/5	0/5
		5 females	0/5	0/5	0/5	0/5
206	2	5 males	0/5	0/5	0/5	0/5
		5 females	0/5	0/5	0/5	0/5

Interpretation of results:

GHS criteria not met

Endpoint conclusion

Endpoint conclusion:

adverse effect observed

Dose descriptor:

LD50

Value:

5 150 mg/kg bw

Quality of whole database:

Comparable to guideline study.

Acute toxicity: via inhalation route

Link to relevant study records

Reference

Endpoint:

acute toxicity: inhalation

Type of information:

experimental study

Adequacy of study:

key study

Study period:

05 May - 10 June 1980

Reliability:

2 (reliable with restrictions)

Rationale for reliability incl. deficiencies:

study well documented, meets generally accepted scientific principles, acceptable for assessment

Qualifier:

equivalent or similar to guideline

Guideline:

OECD Guideline 403 (Acute Inhalation Toxicity)

Principles of method if other than guideline:

Inhalation Risktest as in Annex 1 of OECD 403; method based on the publication by Smyth HF et. al. (1962). Am. Ind. Hyg. Ass. J. 23: 95-107.

GLP compliance:

no

Test type:

other: inhalation risk test

Limit test:

yes

Species:

rat

Strain:

Sprague-Dawley

Sex:

male/female

Details on test animals or test system and environmental conditions:

TEST ANIMALS
- Source: Fa . Wiga Versuchstieranstalt, Sulzfeld
- Strain: Caw-Ico-Wiga (SPF)
- Age at study initiation: 7 - 10 weeks
- Weight at study initiation: males: 180 - 250 g; females: 180 - 250 g
- Housing: 3 animals/cage
- Diet (ad libitum): Herilan MRH as pellets (EGGERSMANN KG, Rinteln)
- Water (ad libitum): dailyapprox. 250 mL tap water/cage
- Acclimation period: at least 5 days


ENVIRONMENTAL CONDITIONS
- Temperature: 22 ± 2 °C
- Humidity: 50 + 5 %
- Photoperiod (hrs dark / hrs light): 12 h/12 h

Route of administration:

inhalation: vapour

Type of inhalation exposure:

whole body

Vehicle:

other: unchanged (no vehicle)

Details on inhalation exposure:

GENERATION OF TEST ATMOSPHERE / CHAMBER DESCRIPTION
The product was filled in a column of about 5 cm above a fritted glass disc in a glass cylinder (diameter 30 mm) placed in a water bath at 20 ± 1 °C. Fresh air was bubbled at a rate of 200 L/h through the substance column generating a highly saturated substance-vapour-mixture which was led through six glass tubes containing 3 male and female test animals. Exhaust air was disposed of. In case of exposure periods above 30 min, the substance column was replaced after 30 min by a newly filled column. This column was then used for the remaining exposure period. In case the substance in the glass column was spent well before the end of the first 30 min, the substance column was refilled as often as needed to ensure a constant substance-vapour-mixture at least within the first 30 min. The amount of test substance used in the system was determined at the end of the exposure period by weighing.

Analytical verification of test atmosphere concentrations:

no

Duration of exposure:

7 h

Concentrations:

mean: 155 mg/L (corresponding to 43 000 ppm)

No. of animals per sex per dose:

3

Control animals:

no

Details on study design:

- Duration of observation period following administration: 14 days
- Frequency of observations and weighing: Body weights were determined only at test start.
- Necropsy of survivors performed: yes
- Other examinations performed: clinical signs, gross-pathological examination

Key result

Sex:

male/female

Dose descriptor:

LC0

Effect level:

ca. 155 mg/L air (nominal)

Exp. duration:

1 h

Mortality:

1 h exposure: 0/12
3 h exposure: 6/12
7 h exposure: 4/18

Clinical signs:

other: Vigorous flight attempts, dyspnoea, red eye discharge, eye lids adhering, crust formation on nose, complete closure of the eye lids, snout wiping, loss of the lid reflex, narcosis, apathy, squatting posture, ruffled fur, staggering, halting, high stepping

Body weight:

no data

Gross pathology:

Deceased animals:
- Heart: acute dilatation
- Stomach: multiple, hemorrhagic erosions, bloody stomach contents
- Lungs: acute pulmonary emphysema
- Intestines: bloody faeces in some sections, atonic, diarrheic contents

Sacrificed animals:
- without findings

Mortality:

Exposure time [h]	1	3	7
No. of dead / no. of treated animals	0/12	6/12	4/18

Interpretation of results:

GHS criteria not met

Endpoint conclusion

Endpoint conclusion:

adverse effect observed

Dose descriptor:

discriminating conc.

Value:

38 750 mg/m³ air

Quality of whole database:

Comparable to guideline study.

Acute toxicity: via dermal route

Endpoint conclusion

Endpoint conclusion:

no study available

Additional information

There are no human data on acute toxicity of 1,4-dioxane available.
The acute toxicity of 1,4 -dioxane in animals is low. The available BASF studies on acute oral and inhalation toxicity were selected as the key studies as they were performed using methods comparable to the relevant OECD guidelines.

The oral LD50 was 5150 mg/kg bw in rats in a well conducted study.

In a whole body inhalation study performed with Sprague Dawley rats the LC0 for 1 hour exposure was ca. 155 mg/L air (nominal). Extrapolation of this value to 4 hour exposure can be performed. According to Chapter R.8 of REACH Technical Guidance Document, if time extrapolation is considered valid, then the most appropriate approach is to make use of the modified Haber’s law (Cⁿx t = k, where ‘C’ is the concentration, ‘n’ is a regression coefficient,‘t’ is the exposure time and ‘k’ is a constant). A default value of n=1 is suggested for extrapolating from shorter to longer exposure durations. Therefore, the recalculated LC0 for 4 hours exposure is 38.75 mg/L.

Clinical signs and gross pathological findings of deceased animals indicate that adverse effects may be a result of mucosal irritation induced by the test item.

Only limited data regarding the dermal route of exposure is available, also showing low toxicity. However, in accordance with column 2 Section 8.5 of REACH Annex VIII-X, no dermal acute toxicity study is required as data for the oral and inhalation route are available.

Justification for classification or non-classification

Classification, Labelling, and Packaging Regulation (EC) No 1272/2008
The available experimental test data are reliable and suitable for classification purposes under Regulation (EC) No 1272/2008. The oral LD50 was greater than 2000 mg/kg bw. The inhalation LC0 was re-calculated to be 38.75 mg/L. As a result the substance does not require classification for acute oral or inhalation toxicity under Regulation (EC) No 1272/2008, as amended for the twelfth time in Regulation (EU) 2019/521.

Classification concerning acute dermal toxicity is also not warranted.

The test item is legally classified as STOT SE 3 (H335: "May cause respiratory irritation") according to Annex VI of Regulation (EC) No 1272/2008 (CLP Regulation).